Host defense-derived
peptides have emerged as a novel strategy for the development of alternative anticancer
therapies. In this study we report on characteristic features of human
lactoferricin (hLFcin) derivatives which facilitate specific killing of
cancer cells of
melanoma,
glioblastoma and
rhabdomyosarcoma compared with non-specific derivatives and the synthetic
peptide RW-AH. Changes in amino acid sequence of hLFcin providing 9-11
amino acids stretched derivatives LF11-316, -318 and -322 only yielded low antitumor activity. However, the addition of the repeat (di-
peptide) and the retro-repeat (di-retro-
peptide) sequences highly improved
cancer cell toxicity up to 100% at 20 μM
peptide concentration. Compared to the complete parent sequence hLFcin the derivatives showed toxicity on the
melanoma cell line A375 increased by 10-fold and on the
glioblastoma cell line U-87mg by 2-3-fold. Reduced killing velocity, apoptotic blebbing, activation of
caspase 3/7 and formation of apoptotic
DNA fragments proved that the active and
cancer selective
peptides, e.g. R-DIM-P-LF11-322, trigger apoptosis, whereas highly active, though non-selective
peptides, such as DIM-LF11-318 and RW-AH seem to kill rapidly via
necrosis inducing membrane lyses. Structural studies revealed specific toxicity on
cancer cells by
peptide derivatives with loop structures, whereas non-specific
peptides comprised α-helical structures without loop. Model studies with the
cancer membrane mimic
phosphatidylserine (PS) gave strong evidence that PS only exposed by
cancer cells is an important target for specific hLFcin derivatives. Other negatively charged membrane exposed molecules as
sialic acid, heparan and
chondroitin sulfate were shown to have minor impact on
peptide activity.